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Inflammasome and Gasdermin Signaling Networks for Regulation of Pyroptosis and Cytokine Release

用于调节焦亡和细胞因子释放的炎性体和 Gasdermin 信号网络

基本信息

批准号：
10654563
负责人：
GEORGE R DUBYAK
金额：
$ 188.67万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654563
关键词：
Acute Alzheimer&apos s Disease Amyloid Apoptosis Apoptotic Autophagocytosis Biochemical Biochemistry CASP1 gene CASP3 gene CASP8 gene CASP9 gene Caspase Categories Cell Death Cell Lineage Cell membrane Cell physiology Cells Cellular biology Chaperone Protein Interaction Chronic Compensation Complex Crohn&apos s disease Cytolysis DNA Disease Disease model Dissociation Dysmyelopoietic Syndromes Effector Cell Elements Epithelial Cells Extracellular Space Familial Mediterranean Fever Functional disorder Genetic Goals Golgi Apparatus Immune Immune response Immunologics Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Interleukin-1 beta Investigation Link Literature Lytic Macrophage Mediating Mediator Membrane Molecular Multiple Sclerosis Mus Myeloid Cells Myocardial Infarction N-terminal Necrosis Nonlytic Pathogenesis Pathogenicity Pathway interactions Peptide Hydrolases Peptide Signal Sequences Population Production Proteins Publishing Reagent Regulation Reporting Secretory Vesicles Signal Transduction Source Sterility Stimulus T-Lymphocyte Testing Tissues Ulcerative Colitis VDAC1 gene cell killing cell type cytokine extracellular gastrointestinal granulocyte gut inflammation human disease intestinal epithelium microbial mouse model neutrophil novel programs response restraint structural biology structural determinants trafficking

项目摘要

OVERALL PROGRAM PROJECT: ABSTRACT Cell death pathways have historically been characterized by the proteases that become activated during cell fate decisions. Apoptosis has been defined by initiator and effector caspase activation and, largely due to the reagents available; cell death decisions were initially thought to be binary – caspase-dependent (apoptosis) or caspase-independent (all others). Much like other binary distinctions – like Th1 versus Th2 T cells or M1 versus M2 macrophages, which have undergone substantial expansion in the past decade, cell death decisions and their consequences are now recognized to be much more variables. In fact, even the mechanisms of cell death have been refined. They are no longer categorized by the proteases which activate the cascades but rather, by the effector mechanism. Necroptotic cell death is caused by activation of the pore-forming protein, MLKL. Secondary necrosis is caused by activation of the pore-forming protein, DFNA5 (Gasdermin E/GSDME), and pyroptosis is caused by activation of the pore-forming protein, Gasdermin D (GSDMD) This last category of cell death - pyroptosis - is one of the most immunologically important forms of cell death. Not only does pyroptosis kill the cell, but also GSDMD activation allows the release of IL-1β. This cytokine is among the most important in acute and chronic inflammation. Its secretion is implicated in rare genetic inflammatory diseases such as Familial Mediterranean Fever as well as more common diseases such as myocardial infarction, Alzheimer's disease, Crohn's disease and Ulcerative Colitis, Multiple Sclerosis and many others. With the discovery of the inflammasome in 2002 and its subsequent study, it became clear that the amyloid-like activation of these inflammasome complexes drove pro-IL-1β cleavage and IL-1β release from the cell, but also pyroptosis. Missing from this biochemistry, though, was the cell biology underlying IL-1β release. How is IL- 1β recognized by caspases and other proteases? If IL-1β is not released through a secretory ER-Golgi mechanism, how is trafficked out of the cell? How is this release coordinated with pyroptosis and other regulated cell death pathways that are operative in different populations of immune effector cells. This Program Project aims to utilize cell physiology, biochemistry, structural biology, and mouse and human disease models to unravel these important questions.

总体方案方案：摘要

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.

DOI：
10.15252/embj.2022110780
发表时间：
2023-01-04
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Liao, Yun;Chen, Xing;Miller-Little, William;Wang, Han;Willard, Belinda;Bulek, Katarzyna;Zhao, Junjie;Li, Xiaoxia
通讯作者：
Li, Xiaoxia

The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.

DOI：
10.1002/1878-0261.13447
发表时间：
2023-12
期刊：
MOLECULAR ONCOLOGY
影响因子：
6.6
作者：
Luo, George;Aldridge, Kristin;Chen, Toby;Aslot, Vivek;Kim, Byung-Gyu;Han, Eun Hyang;Singh, Neelima;Li, Sai;Xiao, Tsan Sam;Sporn, Michael B.;Letterio, John J.
通讯作者：
Letterio, John J.

Partners with a killer: Metabolic signaling promotes inflammatory cell death.